In the treatment of a patient by the administration of oral medication it is desirable to administer a single dose of the selected drug, the drug being released over an extended of period of time rather than administering several doses at regular intervals. Many sustained release formulations are known in the pharmaceutical art, which formulations are intended to continuously provide drug for absorption while the dosage form passes through the gastrointestinal tract of the patient. The conventional oral dosage form generally releases the active compound in a period of a few minutes to 2 hours after administration, making repeated administration of the dosage form necessary. Thus a sustained release formulation which releases the drug over an extended period of time can be advantageous. However, conventional sustained released formulations which are not retained in the stomach and which release the drug in the intestine are not suitable for medicaments which are principally absorbed from the stomach such as acidic medicament, antacids or prostaglandins.
Prostaglandins are involved in the treatment of the pathogenesis of peptic ulcer disease. They inhibit gastric secretion in man. These antisecretory effects appear to involve a direct action on stomach parietal cells. A bilayer floating dosage form is proposed to improve stomachal delivery of prostaglandins or derivatives thereof and misoprostol in particular. This should reinforce local action of prostaglandins on the parietal cells and reduce any side effects appearing when the drug is massively delivered in the intestine. Peak effects of prostaglandins will be lowered while continuously providing drug at the action sites.
Several patents describe buoyant dosage forms which improve gastric residence time. Most of these patents disclose monolithic type of dosage forms. U.S. Pat. No. 4,126,672 and U.S. Pat. No. 4,167,558 describe hydrodynamically balanced capsules with a density of less than one that remain buoyant on the gastric fluid. Hydroxypropyl methyl-cellulose (HPMC) and fatty materials are used to regulate flotation and drug release. U.S. Pat. Nos. 4,814,178 and 4,814,179 describe a non-compressed sustained release floating tablet including a hydrocolloid gelling agent, an inert oil, selected therapeutic agents and water and have a network of multitudinous airholes and passages therein and a density of less than 1. U.S. Pat. No. 4,126,672 describes a buoyant capsule dosage form in which HPMC provides the sustained release. The density of the capsules is adjusted by the use of a fatty material so that the capsules float in the gastric fluid. International application No. W085/04100 describes a gastrointestinal sustained release pharmaceutical unit dosage form comprising a non-compressed mixture of a therapeutic agent and a high molecular weight HPMC contained in a gelatin capsule. The formulations employed in this dosage form are described as not tailored to insure buoyancy in gastric fluids and are said to provide sustained release of drug independent of gastro intestinal pH and therefore equally effective both in the stomach and intestine.
A two layer buoyant tablet containing antacids is disclosed in U.S. Pat. No. 4,140,755. In this patent, one layer is formulated to immediately release the active drug and the other layer to acquire a density lower than one in gastric juice and to provide a sustained release of the active drug.
In vivo investigations have been conducted by different investigators, using non-invasive imaging techniques to determine the gastric residence time of the floating dosage form. Conflicting data are reported on the influence of density on the gastric residence time of a dosage form, some authors showing an increased residence time with floating dosage forms, other authors showing equivalence between floating and non-floating dosage form (S. A. Muller-Lisner and A. L. Blum; The new England Journal of Medicine, 304 (22) 1981; P. R. Sheth and J. Tossounian, Drug Dev. Ind. Pharm., 10(2), 313-339 (1984); W. Erni and K. Held Eur. Neurol. 27:suppll. 1 21-27 (1987); N. Mazer et al. J. of Pharm. Sci., 77 (8) 647-657 (1988); H. M. Ingani et al., Int. J. Pharm.,. 35 157-164 (1987); S. Sangekar et al., Int. J. Pharm.; 35 187-191 (1987); J. Timmermans et al., 5th International Conference on pharmaceutical Technology APGI, 1 42-51 (1989)).
It is believed the gastric residence time of a buoyant unit not only depends on the initial density but, just as importantly, on the evolution of the density as a function of time.
Other authors have shown that the gastric residence time not only depends on buoyancy of the dosage form but also on the dosage form diameter (R. Khosla et al., Int. J. of Pharm., 53 107-117 (1989); J. Timmermans et al.; 5th International Conference on Pharmaceutical Technology APGI, 1 42-51 (1989)). In vivo studies performed with buoyant units indicate that a mean gastric residence time ranging between 3 and 4 hours can be obtained with fed subjects if the dosage form has appropriate floating capabilities, a diametral size of at least 8 to 10 mm and does not disintegrate. The concept has been applied to a tablet which swells upon contact with gastric juice, impeding passing through the pylorus opening. This tablet is not described as being buoyant (U.S. Pat. No. 3,574,820).